CV19: Mechanism-based targeting of an RNA processing pathway

This collaborative research project aims to make transformative advances to combat COVID-19/SARS-CoV-2 and other potentially emerging coronaviruses. The COVID-19 is an ongoing pandemic with 577.547 cases resulting in 26.447 deaths as of March 27. 2020. The strikingly high death rate (17%) among all closed cases (157.112) makes the SARS-CoV-2 the deadliest virus in recent history. SARS-CoV-2 is an enveloped. positive-sense single stranded RNA beta-coronavirus with very large and complex RNA genome. The RNA processing is essential to its survival in a host cell. which is performed by three nonstructural proteins (nsp13. nsp14. and nsp16). The resulting cap modification of viral RNA by these proteins mimic cellular mRNA to protect it from innate immune restriction and host degradation. Ablation of these activity reduces pathogenesis in vivo and infection with nsp-defective SARS-CoV-1 protects mice from an otherwise lethal viral challenge. These features make nsp proteins of SARS-CoV-1/2 attractive antivirals targets. Our structural data has motivated us to pursue mechanistic studies and develop novel antiviral therapies against COVID-19. We have already identified crucial factors for targeted therapies and will combine biochemical. structural. in silico. artificial intelligence/machine leaning. medicinal chemistry. in vitro and in vivo approaches for the identification of antivirals. To that end. we have assembled an outstanding team from 4 San Antonio institutions; Dr. Gupta (UTHSA. lead-PI). Dr. Martinez-Sobrido (Texas Biomed). Drs. McHardy and Frantz (UTSA); and Drs. Bohman and Ibaroudene (SwRI) to make transformative advances to combat COVID-19/SARS-CoV-2 and other potentially emerging coronaviruses.